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2017 ; 16
(1
): 44
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ITIH5 mediates epigenetic reprogramming of breast cancer cells
#MMPMID28231808
Rose M
; Kloten V
; Noetzel E
; Gola L
; Ehling J
; Heide T
; Meurer SK
; Gaiko-Shcherbak A
; Sechi AS
; Huth S
; Weiskirchen R
; Klaas O
; Antonopoulos W
; Lin Q
; Wagner W
; Veeck J
; Gremse F
; Steitz J
; Knüchel R
; Dahl E
Mol Cancer
2017[Feb]; 16
(1
): 44
PMID28231808
show ga
BACKGROUND: Extracellular matrix (ECM) is known to maintain epithelial integrity.
In carcinogenesis ECM degradation triggers metastasis by controlling migration
and differentiation including cancer stem cell (CSC) characteristics. The
ECM-modulator inter- ?-trypsin inhibitor heavy chain family member five (ITIH5)
was recently identified as tumor suppressor potentially involved in impairing
breast cancer progression but molecular mechanisms underlying its function are
still elusive. METHODS: ITIH5 expression was analyzed using the public TCGA
portal. ITIH5-overexpressing single-cell clones were established based on T47D
and MDA-MB-231 cell lines. Colony formation, growth, apoptosis, migration, matrix
adhesion, traction force analyses and polarization of tumor cells were studied in
vitro. Tumor-initiating characteristics were analyzed by generating a metastasis
mouse model. To identify ITIH5-affected pathways we utilized genome wide gene
expression and DNA methylation profiles. RNA-interference targeting the
ITIH5-downstream regulated gene DAPK1 was used to confirm functional involvement.
RESULTS: ITIH5 loss was pronounced in breast cancer subtypes with unfavorable
prognosis like basal-type tumors. Functionally, cell and colony formation was
impaired after ITIH5 re-expression in both cell lines. In a metastasis mouse
model, ITIH5 expressing MDA-MB-231 cells almost completely failed to initiate
lung metastases. In these metastatic cells ITIH5 modulated cell-matrix adhesion
dynamics and altered biomechanical cues. The profile of integrin receptors was
shifted towards ?1-integrin accompanied by decreased Rac1 and increased RhoA
activity in ITIH5-expressing clones while cell polarization and single-cell
migration was impaired. Instead ITIH5 expression triggered the formation of
epithelial-like cell clusters that underwent an epigenetic reprogramming. 214
promoter regions potentially marked with either H3K4 and /or H3K27 methylation
showed a hyper- or hypomethylated DNA configuration due to ITIH5 expression
finally leading to re-expression of the tumor suppressor DAPK1. In turn,
RNAi-mediated knockdown of DAPK1 in ITIH5-expressing MDA-MB-231 single-cell
clones clearly restored cell motility. CONCLUSIONS: Our results provide evidence
that ITIH5 triggers a reprogramming of breast cancer cells with known stem CSC
properties towards an epithelial-like phenotype through global epigenetic changes
effecting known tumor suppressor genes like DAPK1. Therewith, ITIH5 may represent
an ECM modulator in epithelial breast tissue mediating suppression of tumor
initiating cancer cell characteristics which are thought being responsible for
the metastasis of breast cancer.
|*DNA Methylation
[MESH]
|Animals
[MESH]
|Breast Neoplasms/*genetics
[MESH]
|Cell Line, Tumor
[MESH]
|Death-Associated Protein Kinases/*genetics
[MESH]
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